The combined central theme of this project is a combined Molecular/cellular effort to elucidate the fundamental processes regulated by extracellular molecules during limb morphogenetic tissue interactions. Five independent but related research component projects and a supporting core unit for monoclonal antibody preparation are proposed. These are: a) Project I: "Extracellular Proteins in limb mesenchyme development" relates specifically to ectodermally-derived proteins and their potential role in the positional and overt cytodifferentiation of subpopulations of mesenchyme; b) Project II: "Histone variants in limb development", seeks to identify the histones of active genes during differentiation of the major limb tissue types and any modifications following treatment with ectodermal proteins or endogenous, extracellular proteins; c) Project III: "Muscle-specific ECM components in limb development", seeks to identify tissue specific molecules in the basal lamina of developing myogenically-committed mesenchyme and to define their functional roles: d) Project IV: "Extracellular proteases in limb development: Cell Migration", will examine the role of extracellular proteases in the formation of somite-derived limb mesenchyme; e) Project V:"Vascular influences on limb patterning", considers extracellular proteins derived from the other projects as well as other angiogenic factors in limb vasculogenesis and teratogenesis. The Core Unit is requested to expand our departmental monoclonal facility to accomodate the needs of all research proposed projects. Our enthusiasm for a program project effort stems from a collective desire of the applicants to extend their varied expertises and experiences in developmental/cellular phenomena to a specific tissue/organ level, like the limb system. This Program Project represents interdisciplinary approaches absolutely essential to elucidate mechanisms. The unique mix of talents and expertise in molecular/cellular biology, experimental embryology, clinical medicine and teratology, all predominately in the same academic department (Anatomy), should almost certainly yield a greater resolution to the problems and is certain to be synergistic in approach and in results.